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Depth of the Steroid Core Location Determines the Mode of Na,K-ATPase Inhibition by Cardiotonic Steroids

التفاصيل البيبلوغرافية
العنوان: Depth of the Steroid Core Location Determines the Mode of Na,K-ATPase Inhibition by Cardiotonic Steroids
المؤلفون: Artem M. Tverskoi, Yuri M. Poluektov, Elizaveta A. Klimanova, Vladimir A. Mitkevich, Alexander A. Makarov, Sergei N. Orlov, Irina Yu. Petrushanko, Olga D. Lopina
المصدر: International Journal of Molecular Sciences, Vol 22, Iss 24, p 13268 (2021)
بيانات النشر: MDPI AG, 2021.
سنة النشر: 2021
المجموعة: LCC:Biology (General)
LCC:Chemistry
مصطلحات موضوعية: cardiotonic steroids, Na,K-ATPase, inhibition mode, structural changes, cardiotonic steroids-binding site, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: Cardiotonic steroids (CTSs) are specific inhibitors of Na,K-ATPase (NKA). They induce diverse physiological effects and were investigated as potential drugs in heart diseases, hypertension, neuroinflammation, antiviral and cancer therapy. Here, we compared the inhibition mode and binding of CTSs, such as ouabain, digoxin and marinobufagenin to NKA from pig and rat kidneys, containing CTSs-sensitive (α1S) and -resistant (α1R) α1-subunit, respectively. Marinobufagenin in contrast to ouabain and digoxin interacted with α1S-NKA reversibly, and its binding constant was reduced due to the decrease in the deepening in the CTSs-binding site and a lower number of contacts between the site and the inhibitor. The formation of a hydrogen bond between Arg111 and Asp122 in α1R-NKA induced the reduction in CTSs’ steroid core deepening that led to the reversible inhibition of α1R-NKA by ouabain and digoxin and the absence of marinobufagenin’s effect on α1R-NKA activity. Our results elucidate that the difference in signaling, and cytotoxic effects of CTSs may be due to the distinction in the deepening of CTSs into the binding side that, in turn, is a result of a bent-in inhibitor steroid core (marinobufagenin in α1S-NKA) or the change of the width of CTSs-binding cavity (all CTSs in α1R-NKA).
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1422-0067
1661-6596
Relation: https://www.mdpi.com/1422-0067/22/24/13268; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067
DOI: 10.3390/ijms222413268
URL الوصول: https://doaj.org/article/0d43722bfab145909cf5d9a1e94c8612
رقم الأكسشن: edsdoj.0d43722bfab145909cf5d9a1e94c8612
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:14220067
16616596
DOI:10.3390/ijms222413268